Dual mass spectrometry imaging and spatial metabolomics to investigate the metabolism and nephrotoxicity of nitidine chloride  

作　　者：Shu Yang Zhonghua Wang Yanhua Liu Xin Zhang Hang Zhang Zhaoying Wang Zhi Zhou Zeper Abliz 

机构地区：[1]School of Pharmacy,Minzu University of China,Beijing,100081,China [2]Key Laboratory of Mass Spectrometry Imaging and Metabolomics(Minzu University of China),National Ethnic Affairs Commission,Beijing,100081,China [3]Center for Imaging and Systems Biology,College of Life and Environmental Sciences,Minzu University of China,Beijing,100081,China [4]Key Laboratory of Ethnomedicine of Ministry of Education,School of Pharmacy,Minzu University of China,Beijing,100081,China

出　　处：《Journal of Pharmaceutical Analysis》2024年第7期1011-1023,共13页药物分析学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant No.:21927808);the National Key Research and Development Program of China(Grant No.:2017YFC1704006).

摘　　要：Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development.In this study,we present an innovative,integrated approach that combines air flowassisted desorption electrospray ionization mass spectrometry imaging(AFADESI-MSI),time-of-flight secondary ion mass spectrometry(ToF-SIMS),and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride(NC),a promising anti-tumor drug candidate.Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney,particularly within the inner cortex(IC)region,following single and repeated dose of NC.High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule.Employing spatial metabolomics based on AFADESI-MSI,we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure.These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters(organic cation transporters,multidrug and toxin extrusion,and organic cation transporter 2(OCT2)),metabolic enzymes(protein arginine N-methyltransferase(PRMT)and nitric oxide synthase),mitochondria,oxidative stress,and inflammation in NC-induced nephrotoxicity.This study offers novel insights into NC-induced renal damage,representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.

关 键 词：Nitidine chloride NEPHROTOXICITY Mass spectrometry imaging Spatial metabolomics TOXICOKINETICS 

分 类 号：R96[医药卫生—药理学]